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    Summary
    EudraCT Number:2021-005617-14
    Sponsor's Protocol Code Number:CLEE011Q12101
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2023-02-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2021-005617-14
    A.3Full title of the trial
    Phase I/II multicenter study to assess efficacy and safety of ribociclib (LEE011) in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory neuroblastoma and other solid tumors
    Multicentrické klinické hodnocení fáze I/II k vyhodnocení účinnosti a bezpečnosti ribociklibu (LEE011) v kombinaci s topotekanem a temozolomidem (TOTEM) u pediatrických pacientů s relabovaným nebo refrakterním neuroblastomem a jinými solidními nádory
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess safety and identify dose of ribociclib in combination of temozolomide and topotecan (TOTEM) in patients (12 months – 21 years old) with relapsed or refractory solid tumors (Phase I), and further assess efficacy and safety in patients (12 months – 21 years old) with relapsed or refractory neuroblastoma (Phase II)
    A.4.1Sponsor's protocol code numberCLEE011Q12101
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/020/2022
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis s.r.o.
    B.5.2Functional name of contact pointInformační služba – klin. hodnocení
    B.5.3 Address:
    B.5.3.1Street AddressNa Pankráci 1724/129
    B.5.3.2Town/ cityPraha 4
    B.5.3.3Post code140 00
    B.5.3.4CountryCzechia
    B.5.4Telephone number+420 2 25775 111
    B.5.5Fax number+420 2 25775 205
    B.5.6E-maildotazy.klinickehodnoceni@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameribociclib
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRibociclib
    D.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number204.082
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametemozolomide
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametopotecan
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTOPOTECAN HYDROCHLORIDE
    D.3.9.1CAS number 119413-54-6
    D.3.9.3Other descriptive nameTopotecan
    D.3.9.4EV Substance CodeSUB04921MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    relapsed or refractory neuroblastoma and other solid tumors (including medulloblastoma, high grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma) in patients from 12 months to 21 years old
    E.1.1.1Medical condition in easily understood language
    Recurrent solid tumors in patients from 12 months to 21 years old
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I - part A: To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
    Phase I - part B: To evaluate antitumor activity as assessed by Overall Response Rate (ORR) of ribociclib in combination with TOTEM.
    Phase II: To evaluate the treatment effect as assessed by ORR of ribociclib in combination with TOTEM versus placebo plus TOTEM.
    E.2.2Secondary objectives of the trial
    Phase I – part A:
    • to characterize the safety and tolerability of ribociclib in combination with TOTEM (ribociclib+TOTEM)
    • to characterize the pharmacokinetics (PK) of ribociclib+TOTEM
    Phase I – part B:
    • to assess the antitumor activity of ribociclib+TOTEM as assessed by Duration of response (DOR), PFS, Time to response (TTR), and OS.
    • to characterize the safety and tolerability of ribociclib+TOTEM
    • to characterize the PK of ribociclib+TOTEM
    Phase II:
    • to assess the treatment effect of ribociclib+TOTEM as assessed by PFS and DOR versus placebo plus TOTEM.
    • to assess the treatment effect of ribociclib+TOTEM as assessed by TTR, Clinical Benefit Rate, and OS versus placebo plus TOTEM.
    • to characterize the PK of ribociclib+TOTEM.
    • to characterize the safety and tolerability of ribociclib+TOTEM.
    • to describe the effect of ribociclib+TOTEM on Patient Reported Outcomes (PRO).

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed informed consent/assent must be obtained prior to participation in the study. Participants and/or guardian must have the ability to understand and the willingness to sign a written informed consent document.
    2.Age ≥ 12 months and ≤ 21 years at the time of signing consent form.
    3.Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists.
    a. Neuroblastoma (NB) (Phase I and Phase II)
    i. Histologically proven NB as per International Neuroblastoma Staging System (INSS)
    ii. Relapsed: any relapsed or progressed high-risk (HR)-NB
    iii. Refractory high-risk disease: lack of adequate response to frontline therapy that precludes the participant from proceeding to consolidation therapies (e.g. myeloblative chemotherapy)
    iv. Measurable disease by cross sectional imaging and/or evaluable disease (uptake on MIBG scan or FDG PET with or without bone marrow histology) per International Neuroblastoma Response Criteria (INRC).
    v. Imaging confirmed disease recurrence or progression
    vi. Participants must have an available MYCN amplification status before screening.
    b. Medulloblastoma (MB) (Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH).
    c. High-grade glioma (HGG) (Phase I): Note: excluding any low grades (grade I or grade II) such as astrocytoma, oligodendroglioma, or mixed glioneuronal tumors
    i. HGG, not otherwise specified (NOS), WHO Grade III or Grade IV
    ii. Glioblastoma, IDH-wildtype, or IDH-mutant
    iii. Anaplastic astrocytoma, IDH mutant
    iv. Anaplastic oligodendroglioma, IDH mutant
    v. Anaplastic pleomorphic xanthoastrocytoma
    vi. Diffuse midline gliomas, H3 K27-altered
    vii. Diffuse hemispheric glioma, H3 G34-mutant
    viii. Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype
    d. Malignant rhabdoid tumor (MRT) (Phase I): includes diagnoses of atypical teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumor of the kidney (RTK), and other soft tissues as defined by 2 of the 3 following criteria; either (i)+(ii) or (i)+(iii):
    i. Morphology and immunophenotypic panel consistent with rhabdoid tumor
    ii. Loss of SMARCB1 confirmed by immunohistochemistry
    iii. Molecular confirmation of tumor-specific bi-allelic SMARCB1 loss/mutation is encouraged in cases where SMARCB1 immunohistochemistry is equivocal and required if SMARCB1 immunohistochemistry is not available.
    e. Rhabdomyosarcoma (RMS) (Phase I) independent of fusion status and subtype.
    4.Participants with central nervous system (CNS) disease who are on corticosteroids should take stable doses for at least 7 days prior to first dose of ribociclib with no plans for escalation. Note: participants with symptomatic CNS disease who are neurologically unstable or require local CNS-directed therapy to control their CNS disease are not eligible for the study.
    5.Measurable disease per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for MB, MRT and RMS.
    6.Performance status: participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
    a.≤ 16 years: Lansky Play score ≥ 50%
    b.>16 years: Karnofsky performance status ≥ 50% or ECOG < 3
    7.Life expectancy of ≥ 12 weeks at the time of enrollment.
    8.Adequate bone marrow function (bone marrow may be involved with tumor) and organ function defined as:
    a. Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 without growth factor support within 7 days of the test
    b. Platelet count ≥ 75,000/mm3 without support within 7 days of the test
    c. Hemoglobin ≥ 8.0 g/dL (transfusion allowed)
    d. Total bilirubin ≤ 1.5 x ULN for age (in case of Gilbert’s syndrome, ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN for age)
    e. Adequate liver function, defined as total serum bilirubin ≤ 1.5 x ULN AND alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 2.5 x ULN (in case of liver metastases, AST / ALT ≤ 5 x ULN)
    f. Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN based on age/gender normal. In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) must be ≥ 60 mL/min/1.73 m2.
    g. Adequate cardiac function, defined as corrected QTc interval using Fridericia’s correction (QTcF) ≤ 450 ms and shortening fraction (SF) > 29% (> 35% for participants < 3 years) and left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram
    h. The following laboratory values within normal limits or corrected to within normal limits with supplements before first dose of study medication:
    i. Potassium
    ii. Magnesium
    iii. Total calcium (corrected for serum albumin)
    - Other protocol-defined inclusion criteria may apply
    E.4Principal exclusion criteria
    1. Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
    2. Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies.
    3. Concurrent severe and/or uncontrolled concurrent medical conditions that in the Investigator's judgement could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results.
    4. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
    5. History of QTcF prolongation (i.e. QTcF interval of > 450 ms) or QTcF > 450 ms on screening ECG.
    6. Currently taking medications with a known risk to prolong the QT interval or induce TdP that cannot be discontinued or replaced by safe alternative medication.
    7. Currently taking medications that are known strong inducers or inhibitors of CYP3A4/5 cannot be discontinued at least 7 days or 5 half-lives.
    8. Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index that cannot be discontinued at least 7 days or 5 half-lives.
    9. Vaccinated with live, attenuated vaccines within 4 weeks.
    10. Participated in a investigational study within 30 days or 5 half-lives.
    11. Received prior treatment with a CDK4/6 inhibitor.
    12. Received anticancer therapy (including experimental) within 4 weeks.
    13. Received myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks.
    14. Received allogeneic stem cell transplant within 3 months.
    15. Has radiation within 4 weeks (or 2 weeks if radiation therapy is given for palliation), or within 6 weeks of MIBG treatment.
    16. Major surgery within 2 weeks and not recovered fully from the side effects.
    - Other protocol-defined exclusion criteria may apply
    E.5 End points
    E.5.1Primary end point(s)
    Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28-Day cycle)
    Phase I – part B: ORR (percentage of participants with confirmed best overall of CR or PR) as assessed by Blinded Independent Review Committee (BIRC) per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with high-grade glioma (HGG), International Neuroblastoma Response Criteria (INRC) for participants with neuroblastoma (NB), response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with medulloblastoma (MB), malignant rhabdoid tumor (MRT) and rhabdomyosarcoma (RMS)
    Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I – part A: 9 months from trial start until declaring MTD/RP2D
    Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB
    Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled)
    E.5.2Secondary end point(s)
    Phase I – part A:
    • Safety: Incidence, type, and severity of adverse events (AEs) per common terminology criteria for adverse events (CTCAE) version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments, and incidence of DLTs in Cycle 1.
    Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    • Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
    Phase I – part B:
    • DOR, PFS, TTR per RANO criteria for participants with HGG, INRC for participants with NB, RECIST 1.1 for participants with MB, MRT and RMS as assessed by BIRC assessment, and OS.
    • Safety: Incidence, type, and severity of AEs per CTCAE version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments and incidence of DLTs in Cycle 1.
    Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    • Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
    Phase II:
    • PFS and DOR using INRC as assessed by BIRC (key secondary endpoints).
    • TTR, CBR using INRC as assessed by BIRC and OS.
    • Plasma concentrations of ribociclib, topotecan, temozolomide and derived PK parameters of ribociclib such as AUC and Cmax.
    • Safety: Incidence, type, and severity of adverse events per CTCAE version 5.0 criteria including changes in laboratory values, performance status, vital signs, liver assessments and cardiac assessments.
    Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    • PRO as measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I – part A: 9 months from trial start until declaring MTD/RP2D
    Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB
    Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Acceptability, palatability, PRO
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I/II in new population and indication
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Singapore
    United States
    Czechia
    Denmark
    France
    Germany
    Hungary
    Italy
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Study completion is defined as when the last patient finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 230
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 23
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 150
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 55
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 230
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Novartis will make every effort to supply ribociclib to participants who may benefit from continued treatment as per the Investigator’s opinion. After completion of 12 cycles of treatment, in case of ongoing clinical benefit (i.e. stable disease or better) with acceptable toxicity, participants may continue to receive ribociclib alone at the same dose as received in combination with TOTEM until disease progression or occurrence of unacceptable toxicity that precludes any further treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Innovative Therapies for Children with Cancer (ITCC)
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-28
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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